Therapeutic Reversal of Endothelial Dysfunction in Atherogenesis Cardiovascular disease is the leading cause of morbidity and mortality in the world. In particular, atherosclerosis is a life-threatening disease strongly associated with risk factors such as elevated cholesterol levels, high blood pressure and diabetes. There are effective commercially available therapeutics that target these systemic risk factors. Yet despite these, there is still a significant rate of adverse events in patients prescribed these therapeutic and a significant population that suffer adverse cardiovascular events even in the absence of these conventional systemic risk factors. Importantly, in the face of these systemic classical cardiovascular risk factors, certain regions of the arterial vasculature remain relatively resistan to the development of atherosclerotic lesions while some are relatively susceptible. Interestingly, the anatomical locations of these protected and susceptible regions are predictable between individuals and even between species. Multiple lines of evidence suggest that the specific hemodynamic environments within these arterial regions exert a protective influence on the local vascular endothelium, and thus inhibit early lesion development. In contrast, hemodynamic conditions present in other regions of the vasculature evoke a pro- inflammatory pro-atherogenic dysfunctional state in the endothelium. Despite recent progress in the understanding of some of the biological mechanisms responsible for hemodynamics-induced atheroprotection and atherosusceptibility, these basic discoveries have not yet been translated into therapeutic strategies for the treatment of cardiovascular disease. During the Phase I of our STTR funded project, we utilized insights regarding the mechanisms underlying endothelial responses to hemodynamic flow to establish a novel cardiovascular drug discovery platform, which resulted in the identification of novel chemical entities able to mimic hemodynamics-induced atheroprotection. In this Phase II project, we will continue development of these promising results. Here, the major goals are to 1) develop an optimized lead compound from our existing vasoprotective chemical series, 2) characterize the mechanism of action of this vasoprotective compound, and 3) evaluate the preclinical efficacy of this optimized lead in an animal model of atherosclerosis. These essential milestones should catalyze this innovative cardiovascular drug discovery effort toward clinical translation, thus establishing a new approach to cardiovascular disease therapy.